Document zQoj7N0G67QEyX1ro84or1Y13
AR226-3206
TRADE SECRET
Study Title H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Supplement No. 1 Laboratory Project ID: DuPont-2931
AUTHOR: Carol Pinlay, B.A. STUDY COMPLETED ON: August 29, 2001 SUPPLEMENT NO. 1 COMPLETED ON; December 12,2001 PERFORMING LABORATORY: E.I. du Font de Nemours and Company
Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050
WORK REQUEST NUMBER--:Mm1j
SERVICE CODE NUMBER:--------|f
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement No. 1
CERTIFICATION
We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study.
Renewed by;
yi^cl^t^ \J!jtjOUC(^ C. Judith C. ^- Stadler, Ph.D., D.A.B.T.
Diceetor
^->GQ^Od/
Date
/L/L^ Issued by Study Director: ______C
Cat^Fsp^ayu,Bk/.jAO.^^.______ Staff Scientist
f'l -/^^^ ^Z> 6| Date
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TABLE OF CONTENTS
Page
CERTIFICATION........................................................................................................................^
LIST OF TABLES .........................................................................................................................4
LIST OF FIGURES.......................................i........................>.........."4
LIST OF APPENDICES...............................................................................................................4 STUDY INFORMATION ...........................................................................................................5
STUDY PERSONNEL...............................................................................................................-^ REASON FOR SUPPLEMENT NO. 1 ........................................................................................8
SUMMARY..............................................................-...--....--.......................................................9
MATERIALS AND METHODS ................................................................................................10 RESULTS AND DISCUSSION ..................................................................................................10
A. Liver Weights....................................................................................................................10
1. Test Substance.......................... .......................................................................-.....---.--- ............10 2. Positive Controls....................................................................................................................................10
B. Liver Fluorine Data...........................--..............................................................................11
1. Positive Controls..................................--------.................--......................------..............--..................11
2. TestSubstance.................................................................................--.----------------ll
CONCLUSIONS..................................................................................--"."--...........................11
"-
| A' KJ jr^^^^-.-.-.^..-.-.....-.-.B--.a...-a.B.flM..BBP*>*>***"********"-I^
FIGURES ..........,,..............................................................................................."...."--.........16
APPENDICES..............................................................................................................................22
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement No. 1
LIST OF TABLES
Page
1. MEAN BODY AND LIVER WEIGHTS .........................................................................................................13 2. MEAN LIVER FLUORINE LEVELS......................................................--....................................................... 15 3. MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE..................................................15
LIST OF FIGURES
Page
1. COMPARISON OF MEAN RELATIVE LIVER WEIGHTS: TEST SUBSTANCE AND NEGATIVE
17 CONTROLS.......................................................................................................................--..............................
2. COMPARISON OF MEAN RELATIVE LIVER WEIGHTS: TEST SUBSTANCE AND POSITIVE CONTROLS....................................................................................................................................................... -18
3. COMPARISON OF RELATIVE LIVER WEIGHT AND MEAN LIVER FLUORINE CONCENTRATION FOR H-24042 AND NEGATIVE CONTROLS.........................................--............--.--............................19
4. MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE.......--.......................---- -20 5. COMPARISON OF MEAN BLOOD AND MEAN LIVER FLUORINE CONCENTRATION
NORMALIZED TO DOSE........................................--...........----.....--......----...------...................... --21
LIST OF APPENDICES
Page
A. INDIVIDUAL FINAL BODY WEIGHTS, LIVER WEIGHTS, AND RELATIVE LIVER TO BODY WEIGHT--...........................................----.......--...................-.......--..................................--.--. .........23
B. INDIVIDUALFLUORINELEVELS............................................................--.......----....--.--..........---- ..34
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
STUDY INFORMATION TEST SUBSTANCE:
Substance Tes
Haskell Number: 24042 Compositi
DuPont-2931 Supplement No. 1
Known Impurities: Poly(difluoromethylene), alpha-fluoro-omega-(2-iodoethyl)(2-3%)
Physical Characteristics: Pale yellow to amber brown waxy solid
POSITIVE CONTROL: Substance Tested!
Synonyms/Codes:
Haskell Number: 24019
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Known Impurities: Unknown
POSITIVE CONTROL:
Known Impurities: Unknown
Sponsor:
E. I. du Font de Nemours and Company Wilmington, Delaware 19898
U.S.A.
Study Initiated/Completed: April 30,1999 / (see report cover page)
In-Life Initiated/Completed: June 13,1999 / September 14,1999
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Stady in Rats
STUDY PERSONNEL
Study Director:
Management: Primary Technician:
Carol Finlay, B.A. Judith C. Stadler, Ph.D., D.A.B.T. Richard P. Mathena
liver Fluorine Data Analysis: Paul M. Hinderiiter, Ph.D.
Management: Matthew S. Bogdanffy, Ph.D., D.A.B.T.
Toxicology Report Preparation: Wanda F. Dinbokowitz
Laboratory Veterinarian: Wanda L. West, D.V.M., A.C.L.A.M.
DuPont-2931 Supplement No. 1
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement No. 1
REASON FOR SUPPLEMENT NO. 1
The purpose of this supplement is to present the results from analysis of selected liver samples from rats treated with the test substance (H-24042), 2 positive controls (H-24019 and H-24020), and 2 negative controls (corn oil and corn oil/acetone).
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SUMMARY
The objective of this study was to evaluate the potential for H-24042, when administered by gavage, to be absorbed and to accumulate in a mammalian system. Six groups of 5 male
Cri:CD(SD)IGSBR rats each were given 100 mg/kg/day of H-24042. The test substance was
administered to one group of 5 rats for 5 consecutive days and to 5 groups for 10 days. On
selected days (5,10,13,24,52,94) 5 rats per group were euthanized and the blood and livers were collected, livers were weighed and those collected on study days 10 and 94 were analyzed for total fluorine. This supplement includes liver weight data and the results of total fluorine
analyses in liver. Additionally, 2 negative controls, corn oil and corn oiVacetone (80:20), and 2 positive controls, H-24019 (10 mg/kg/day) and H-24020 (20 mg/kg/day), were tested as described for H-24042.
The mean relative liver weight (liver/body weight) of rats dosed with the test substance, H-24042, was up to 39% higher at day 10 than the mean relative liver weights of the negative control groups. By day 94, the mean relative liver weight of rats dosed with the test substance was similar to the negative controls. On day 10, the mean relative liver weight of rats dosed with the positive control H-24019 was up to 27% higher than the negative controls. By day 94, the mean relative liver weight was up to 28% higher than the negative controls. In rats given H-24020, the mean relative liver weight was up to 75% higher than the negative controls. By day 94, the weights were similar.
The concentration of fluorine in the livers from rats dosed with the test substance, H-24042, was
271.39 pM equivalents on day 10 and 15.15 piM equivalents on day 94. On day 10, mean [iM
equivalent concentrations of fluorine in the livers from rats dosed with the positive control materials were approximately 18-fold (H-24019) and 4-fold (H-24020) greater than the fluorine concentration in livers from rats treated with the test substance. By day 94, the fluorine concentration in rats dosed with the positive control H-24019 was approximately 80x the fluorine concentration in rats treated with H-24042. The fluorine concentration in rats dosed with the positive control H-24020 and test substance H-24042 was similar by day 94.
The IJI.M equivalents of fluorine in the livers from rats dosed with the test substance, H-24042, were higher than levels in the blood.
Under the conditions of this study, there was some absorption and retention of fluorine in the liver from rats dosed with H-24042. Fluorine levels in the livers from rats dosed with the test substance were lower than levels in rats dosed with the positive control H-24019. Fluorine levels in the livers from rats dosed with the test substance were lower on day 10 than levels in rats dosed with the positive control H-24020. On day 94, the fluorine levels were similar. liver weights were elevated in rats dosed with the test substance, H-24042, at the end of the dosing period, but not at the end of the recovery period.
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement No. 1
MATERIALS AND METHODS
Blood and livers were collected on days 5,10,13,24, 52, and 94. The livers were weighed. Only the test day 10 and 94 livers were analyzed for total fluorine. These time points provided
sufficient data to determine the accumulation and persistence of fluorine in the liver. See the original report for details of the analysis.
RESULTS AND DISCUSSION
A.
Liver Weights
(Table 1, Figures 1-3, Appendix A)
As with the body weights, comparison of absolute liver weights was complicated by the fact that there was a difference in age between rats dosed with the test substance and those dosed with the H-24019 positive control and corn oil:acetone negative control. Therefore, liver weights relative to total body weight are presented for comparison for all rats.
1.
Test Substance
The mean relative liver weight of rats dosed with the test substance, H-24042, was up to 36% higher than the negative controls on day 10. On day 13, the mean relative liver weight of rats dosed with the test substance was up to 48% higher than the negative controls. The weights were similar throughout the remainder of the recovery period.
2.
Positive Controls
The mean relative liver weights of rats dosed with one of the positive controls, H-24019, were slightly lower on days 10 and 13 than the liver weights of rats dosed with the test substance, H-24042. The liver weights of rats dosed with H-24019 were 13-21% higher during the remainder of the recovery period than the liver weights of rats dosed with the test substance. The mean relative liver weight of rats dosed with H-24020, the other positive control, was 26% higher on day 10 than the liver weight of rats dosed with H-24042. On days 13 and 24 (recovery), the mean relative liver weights of rats dosed with H-24020 were 10 or 40% higher than the liver weights of rats dosed with H-24042. On days 52 and 94, the weights were similar.
The mean relative liver weight of rats dosed with H-24019 was up to 27% higher at day 10 than the negative control group. By day 94, the mean relative liver weight of rats dosed with H-24019 was up to 28% higher than the negative controls. The mean relative liver weight of rats dosed with H-24020 was up to 75% higher at day 10 than the negative controls. The mean relative liver weights of rats dosed with H-24020 began to decrease during the recovery period and were similar by test day 94 to the negative controls.
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement No. 1
Therefore, liver weights of rats dosed with the test substance, H-24042, were elevated at the end of the 10-day dosing period. The relative liver weight by the end of recovery in rats dosed with the test substance was lower than in rats dosed with the positive control material H-24019 and similar to rats dosed with the positive control material H-24020.
B.
Liver Fluorine Data
(Tables 2 and 3, Figures 3-5, Appendix B)
1.
Positive Controls
The positive controls were H-24019 and H-24020. The concentrations of fluorine in the livers on day 10 from rats dosed with the positive control materials were 5045.85 and 1127.25 juM equivalents for H-24019 and H-24020, respectively. By day 94, the concentrations were 1190.15
and 10.72 ^M equivalents.
2.
Test Substance
Levels of total fluorine in livers from rats dosed with the test substance, H-24042, were generally lower than the levels in livers from rats dosed with the positive control materials. The total fluorine concentration in the liver from rats dosed with H-24042 was 271.39 fJiM equivalents at day 10 and 15.15 /tM equivalents at day 94. For the positive control H-24019, the liver concentrations were approximately 18x higher (day 10) and approximately 80x higher (end of study) than H-24042. For H-24020, the liver concentration was approximately 4x higher by day 10. The fluorine concentration in rats dosed with the positive control H-24020 and test substance H-24042 was similar by day 94.
The fiM equivalents of fluorine in the livers from rats dosed with the test substance were higher
than levels in the blood.
CONCLUSIONS
Under the conditions of this study, there was some absorption and retention of fluorine in the liver from rats dosed with H-24042. Fluorine levels in the livers from rats dosed with the test substance were lower than levels in rats dosed with the positive control H-24019. Fluorine levels
in the livers from rats dosed with the test substance were lower on day 10 than levels in rats dosed with the positive control H-24020. On day 94, the fluorine levels were similar. Liver weights were elevated in rats dosed with the test substance, H-24042, at the end of the dosing period, but not at the end of the recovery period.
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TABLES -12- Company Sanitized. Does not contain TSCA CBI
H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement No. 1
Test Days 5 10 13 24 52 94
TABLE 1
MEAN BODY AND UVER WEIGHTS (g)
CORN OIL (NEGATIVE CONTROL)
Absolute
Body Weight
liver Weight
259.3
12.620
311.1
15.861
322.9
14.906
391.2
16.635
464.7
17.240
557.8
20.118
Mean Relative
liver Weight(% of Body Weight)
0.049 0.051 0.046 0.043 0.037 0.036
Test Days 5 10 13 24 52 94
CORN OIL:ACETONE (NEGATIVE CONTROL)
Absolute
Body Weight
Liver Weight
313.4
13.632
356.5
15.597
377.6
17.715
423.5
17.172
527.6
21.275
567.8
18.447
Mean Relative
liver Weight(% of Body Weight)
0.043 0.044 0.047 0.041 0.040 0.032
Test Days 5 10 13 24 52 94
H-24019 (POSITIVE CONTROL)
Absolute________
Body Weight
Liver Weight
306.6
15.456
310.1
17.336
344.8
22.049.
387.9
21.313
438.1
19.826
597.9
24.455
Mean Relative
liver Weight(% of Body Weight)
0.050 0.056 0.064 0.055 0.045 0.041
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement No. 1
Test Days
5 10 13
24 52 94
TABLE 1 (Continued)
MEAN BODY AND LIVER WEIGHTS (g)
H-24020 (POSITIVE CONTROL)
Absolute
BodyWeigiht
Liver Weight
244.8
17.052
284.4
21.944
289.1
21.780
370.3
20.619
456.7
17.713
538.7
18.205
Mean Relative Liver Weight(% of Body Weight)
0.070 0.077 0.075 0.056 0.039 0.034
Test Days 5 10 13 24 52 94
H-24042 (TEST SUBSTANCE)
Absolute
Body Weight
Liver Weight
258.9
16.273
286.3
17.575
317.7
21.447
385.2
17.580
480.1
19.048
592.0
20.150
Mean Relative
liver Weight(% of Body Weight)
0.063 0.061 0.068 0.046 0.040 0.034
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TABLE 2 MEAN LIVER FLUORINE LEVELS
Test Days
10 94
Nep;aitivelControls
Corn Oil (ppm)
Corn ( )il:Acetone
(ppm)
<0.2
0.6s1
<0.5 I2
Positive Controls
H-24019 (ppm)
328.18 (19.3)" 77.56 (10.1)
H-24020 (ppm)
155.76 (29.2) 1.68 (0.3)
a One value. Pour of the values were below the level of detection (LOD). b Standard deviation is in parentheses.
Test Substance
H-24042 (ppm)
203.74 (20.45) 11.56 (2.22)
TABLE 3
MEAN LIVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
Test Days
10 94
Positive (controls
H-24019
H-24020
pM. F Equivalents 5045.85 (296.91)3
/iM F Equivalents
1127.25 (211.37)
1190.15 (156.05)
10.72 (2.14)
a Standard deviation is in parentheses.
Test Substance
H-24042
juM F Equivalents 271.39 (27.26) 15.15 (2.96)
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement No. 1
FIGURES
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 1
COMPARISON OP MEAN RELATIVE UVER WEIGHTS: TEST SUBSTANCE AND NEGATIVE CONTROLS
Test Days
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 2 COMPARISON OF MEAN RELATIVE LIVER WEIGHTS:
TEST SUBSTANCE AND POSITIVE CONTROLS
i
^ wij '~**
^ W
^-
I ^ S
3 ls
^ ^
B ^i-'
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURES
COMPARISON OF RELATIVE UVER WEIGHT AND MEAN UVER FLUORINE CONCENT FOR H-24042 AND NEGATIVE CONTROLS
2SO<
150-T
Day 10
Day 13
Day 94
Day 10
1 Cora Oil (Negative Control) Corn OiLAcetone (Negative Control) 13 H-24042 (Test Substance)
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H-24042: Biopersistence Screening, 10-Dose Oral Gavage Study in Rats
FIGURE 4 MEAN LTVER FLUORINE CONCENTRATION NORMALIZED TO DOSE
6000-r
5000-h
4000-4
s 3000
te
20004
1000
Day 10
Day 94
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
FIGURE 5 COMPARISON OF MEAN BLOOD AND MEAN UVER FLUORINE CONCENTRATION NORMALI
Blood / Liver
Blood /Liver
Blood / Liv
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H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement No. 1
APPENDICES
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H-24042: Biopersistence Screening 10-Doss Oral Gavage Study in Rats
DuPont-2931 Supplement No. 1
APPENDIX A Individual Final Body Weights, Liver Weights, and Relative Liver to Body Weight
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H-24042: Biopersistelice Screening 10-Dose Oral Gavage iStudy in Rats
DuPont-2931 Supplement No. 1
CORN OIL (NEGATIVE CONTROL)
TNDJ\fTDUAL FINAL BODY WEIGHTS (g) , LIVER WEIGHTS (<?). AND
RELATIVE L:HFEB. TO BODY WEHGHT OF MALE RATS
Animal Number 627789
627801
627805
627810
627818
Final
Body Wt. 247.7
240.1
283.7
265.0
260.2
GROUP I
Liver Wt. 11.428 12.216
14.081 13.395 11.981
Relative Liver to Body Wt.
0.046
0.051
0.050
0.051
0.046
Test Day
5
5 5 5 5
Animal Number 627793
627797
627799
627800
627808
Final
Body Wt. 283.5
324.2
294.7
331.3
321.8
GROUP II
Liver Wt.
15.292 15.803 14.285 16.344 17.580
Relative Liver to Body Wt. 0.054
0.049
0.048
0.049
0.055
Test Day
10 10
10 10 10
Animal
Number 627796 627806
627807
627809
627816
Final
Body Wt.
322.7
320.3
305.2
336.2
330.2
GROUP III
Liver Wt. 13.404 15.413 14.935 14.967 15.811
Relative Liver to Body Wt.
0.042 0.048 0.049 0.045 0.048
Test Day
13 13
13
13
13
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H-24042: Biopersistciice Screening 10-Dose Oral Gavage:Study in Rats
DuPont-2931 Supplement No. 1
CORN OIL (NEGATIVE CONTROL)
INDI\riDUAL FINAL BODY WEIGHTS (g) ,, LIVER WEIGHTS (gr), AND
RELATIVE L:H7ER TO BODY WEIGHT OF MALE RATS
Animal
Number 627791
627794
627804
627812
627817
Final
Body Wt. 365.6
416.7
378.1
388.4
407.3
GROUP IV
Liver Wt.
15.371 19.105 15.326 16.775 16.600
Relative Liver to Body Wt.
0.042
0.046
0.041
0.043
0.041
Test Day
24
24
24 24 24
Animal Number 627792
627798
627813
627814
627815
Final
Body Wt. 496.8
517.3
416.8
386.9
505.9
GROUP V
Liver Wt. 16.359 19.293 15,234 14.358 20.958
Relative Liver to Body Wt.
0.033
0.037
0.037
0.037
0.041
Test Day
52 52
52 52
52
Animal Number 627795
627811
627819
627820
627821
Final
Body Wt. 485.0
511.6
653.1
618.0
521.5
GROUP VI
Liver Wt. 16.649
17.405 21.828 26.766 17.943
Relative Liver to Body Wt.
0.034
0.034
0.033
0.043
0.034
Test Day
94 94 94
94 94
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H-24042: Biopersistelice Screening 10-Dose Oral Gavage,Study in Rats
DuPont-2931 Supplement No. 1
CORN OILi: ACETONE (MEGAI'IVE CONTROL)
IMDI\FTDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g ), AND
RELATIVE LT\7ER TO BODY WEIIBHT OF MALE RATS
Animal
Mumber 625361
625363
625364
625380
625383
Final
Body Wt. 349.7
286.7
312.0
305.5
313.1
GROUP I
Liver Wt. 16.800 11.236 13.845 13.253 13.026
Relative Liver to Body Wt.
0.048
0.039
0.044
0.043
0.042
Test Day
5 5 5 5 5
Animal
Number 625355
625362
625367
625368
625378
Final
Body Wt. 333.6
332.9
363.8
386.7
365.4
GROUP II
Liver Wt.
14.409 14.363 16.139 17.745 15.328
Relative Liver to Body Wt. 0.043
0.043
0.044
0.046
0.042
Test Day
10
10
10 10 10
Animal
Number 625357
625358
625370 625384
625385
Final
Body Wt.
405.6
340.7
407.0
357.1
377.6
GROUP III
Liver Wt.
20.091 12.954 21.654 16.520 17.355
Relative Liver to Body Wt.
0.050
0.038
0.053
0.046
0.046
Test Day
13
13 13 13 13
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H-24042: Biopersistelace Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement No. 1
CORN OIL^ACETONE (MEGA1;fIVE CONTROL)
iinm/TDUAL FINAL BOOY WEIGHTS (g) ,, LIVER WEIGHTS (giI , AND
RELATIVE LF/ER TO BODY WEIGHT OF MALE RATS
Animal Number 625354
625365
625371
625376
625381
Final
Body Wt. 396.1
459.6
447.3
432.9
381.8
GROUP IV
Liver Wt.
16.383 18.313 17.859 19.168 14.135
Relative Liver to Body Wt. 0.041
0.040
0.040
0.044
0.037
Test Day
24 24 24 24
24
Animal Number 625356
625359
625360 625372
625374
Final
Body Wt. 533.7
530.3
555.4
506.2
512.3
GROUP V
Liver Wt.
20.498 22.901 23.312 21.287 18.378
Relative Liver to Body Wt. 0.038
0.043
0.042
0.042
0.036
Test Day
52 52 52 52 52
Animal
Number 625353
625369
625373
625375
625377
Final
Body Wt. 565.3
514.8
673.7
588.8
496.6
GROUP VI
Liver Wt. 18.655 17.379 20.073 18.869 17.261
Relative Liver to Body Wt. 0.033
0.034
0.030
0.032
0.035
Test Day
94 94 94
94
94
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H-24042: Biopersistelice Screening 10-Dose Oral Gavage,Study in Rats
DuPont-2931 Supplement No. 1
H-2'1019 (POSITIVE ICONTROL)
INDI\?TDUAL FINAL BODY WEIGHTS (g), LIVER WEIGHTS (g), AND
RELATIVE LB/ER TO BODY WEII3HT OF MALE RATS
Animal
Number 625322
625323
625336
625343
625349
Final
Body Wfc. 329.0
298.0
318.1
294.0
293.7
GROUP I
Liver Wt. 16.409 14.830 16.545 13.809 15.685
Relative Liver to Body Wt. 0.050
0.050
0.052
0.047
0.053
Test Day
5 5
5 5 5
Animal Number 625320
625330
625332 625341
625350
Final
Body Wt. 312.1
310.1
318.3
325.6
284-.3
GROUP II
Liver Wt.
18.845 16.343 17.528 18.254 15.709
Relative Liver to Body Wt.
0.060
0.053
0.055
0.056
0.055
Test Day
10 10
10 10 10
Animal
Number 625321
625327
625342
625345
625348
Final
Body Wt. 371.2
355.3
324.4
336.9
336.4
GROUP III
Liver Wt. 22.322 22.259 20.718 24.403 20.541
Relative Liver to Body Wt. 0.060
0.063
0.064
0.072
0.061
Test Day
13 13 13
13 13
'2S' Company Sanitized. Does not contain TSCA CBi
H-24042: Biopersistelice Screening 10-Dose Oral Gavage iStudy in Rats
DuPont-2931 Supplement No. 1
H-2^1019 (POSITIVE CONTROL)
IMDIVriDUAL FINAL BO DY WEIGHTS (g) ,, LIVER WEIGHTS (g ) , AND RELATIVB L:H/ER TO BODY WEIGHT OF MALE RATS
Animal Number 625325
625328
625338
625340
625352
Final
Body Wt. 381.3
423.9
339.9
419.0
375.3
GROUP IV
Liver Wt. 21.479 22.100
18.018 23.131 21.835
Relative Liver to Body Wt. 0.056
0.052
0.053
0.055
0.058
Test Day
24 24 24 24 24
Animal
Number
625324
625329
625333
625334
625344
Final
Body Wt.
447.4
498.1
427.4
426.5
391.0
GROUP V
Liver Wt. 20.900
20.911 20.508 19.144 17.666
Relative Liver to Body Wt. 0.047
0.042
0.048
0.045
0.045
Test Day
52 52 52 52 52
Animal
Number 625326
625335
625346
626347
625351
Final
Body Wt. 577.5
579.5
556.9
638.9
636.8
GROUP VI
Liver Wt. 23.749 21.548 23.945
27.416 25.615
Relative Liver to Body Wt.
0.041
0.037
0.043
0.043
0.040
Test Day
94 94 94 94
94
-29-
Company Sanitized, Does not contain TSCA CBI
H-24042: Biopersistciice Screening 10-Dose Oral Gavage!Study in Rats
DuPont-2931 Supplement No. 1
H-2.4020 (POSITIVE iCONTROL)
INDI\IDUAL FINAL BC>DY WEIGHTS (g) , LIVER WEIGHTS (g ), AMD
RELATIVE LTTOR TO BODY WEII3HT OP MALE RATS
Animal
Number 627756
627767
627771
627773
627777
Final
Body Wt.
237.5
248.6
239.6
262.3
236.0
GROUP I
Liver Wt. 15.360
19.033 16.968 17.629 16.268
Relative Liver to Body Wt. 0.065 0.077 0.071 0.067 0.069
Test Day
5
5
5
5
.
5
Animal Number 627768
627774
627776
627782
627785
Final
Body Wt. 293.5
338.2
254.4
268.2
267.9
GROUP II
Liver Wt. 22.536 27.332 18.821
20.172 20.857
Relative Liver to Body Wt. 0.077
0.081
0.074
0.075
0.078
Test Day
10 10 10 10 10
Animal Number 627758
627763
627764
627787
627788
Final
Body Wt. 308.7
285.8
306.7
234.9
309.4
GROUP III
Liver Wfc. 26.021 22.123 21.526 16.498 22.730
Relative Liver to Body Wt.
0.084 0.077 0.070 0.070 0.073
Test Day
13
13 13 13
13
.30-
Company Sanitized. Does not contain TSCACBI
H-24042: Biopersistence Screening 10-Dose Oral Gavag;e Study in Rats
DuPont-2931 Supplement No. 1
H-2i.1020 (POSITIVE CONTROL)
INDIVIDUAL FINAL BODY WEIGHTS (g),, LIVER WEIGHTS (g), AMD
RELATIVE LI^/ER TO BODY WEIGHT OF MALE RATS
Animal
Mumber
627759
627761
627770
627779
627786
Final
Body Wt. 380.1
359.4
379.8
406.2
326.1
GROUP IV
Liver Wt. 22.707 19.579 19.540 24.858 16.410
Relative Liver to Body Wt.
0.060 0.054 0.051 0.061 0.050
Test Day
24 24 24 24
24
Animal
Mumber
627757 627760
627765
627772
627781
Final
Body Wt.
436.7
456.5
455.6
513.5
421.0
GROUP V
Liver Wt. 16.899
18.240 16.505 20.225 16.695
Relative Liver to Body Wt.
0.039
0.040
0.036
0.039
0.040
Test Day
52 52 52 52 52
Animal Number 627762
627769
627775
627778
627783
Final
Body Wt. 528.6
609.6
552.8
445.3
557.2
GROUP VI
Liver Wt. 17.732 19.324 17.296 15.628 21.044
Relative Liver to Body Wt. 0.034
0.032
0.031
0.035
0.038
Test Day
94 94 94
94 94
-31-
Company Sanitized. Doss not contain TSCA CB1
H-24042: Biopersisterice Screening 10-Dose Oral Gavage;Study in Rats
DuPont-2931 Supplement No. 1
H-:24042 (TEST SUB,STANCE)
INDI\ODUAL FINAL BOOY WEIGHTS (g), LIVER WEIGHTS (g), AND RELATIVE LB7ER TO BODY WEII3HT OP MALE RATS
Animal Number 627295
627298
627300
627302
627311
Final
Body Wt.
278.0
241.9
259.6
257.0
257.9
GROUP I
Liver Wt. 18.201 13.763 16.695 16.611 16.097
Relative Liver
to Body Wt. 0.065 0.057 0.064 0.065 0.062
Test Day
5
5 5 5 5
Animal number 627283
627289
627292
627293
627309
Final
Body Wt. 264.4
277.6
308.6
274.2
306.6
GROUP II
Liver Wt. 15.437 16.911 19.006 16.548 19.975
Relative Liver
to Body Wt. 0.058 0.061 0.062 0.060 0.065
Test Day
10 10 10 10
10
Animal
Number 627285
627288 627294
627301
627304
Final
Body Wt. 314.3
316.5
292.6
343.6
321.4
GROUP III
Liver Wt. 20.897 20.220 19.927 23.344 22.845
Relative Liver to Body Wt. 0.066 0.064 0.068 0.068 0.071
Test Day
13
13
13 13
13
-32-
Company Sanitized. Does not contain TSCACBi
H-24042: Biopersistelice Screening 10-Dose Oral Gavage iStudy in Rats
DuPont-2931 Supplement No. 1
H-;}4042 (TEST SUBSTANCE) INDI\riDUAL FINAL BODY WEIGHTS (g),, LIVER WEIGHTS (g), AND
RELATIVE LI^7ER TO BODY WEIGHT OF MALE RATS
Animal
Number 627279
627282
627286
627287 627299
Final
Body Wt. 368.4
346.2
411.4
396.6
403.6
GROUP IV
Liver Wt. 17.672
13.799 19.798 17.616 19.014
Relative Liver to Body Wt.
0.048 0.040 0.048 0.044 0.047
Test Day
24 24
24 24 24
Animal Number 627290
627296
627306
627307 627310
Final
Body Wt.
438.4
411.4
497.7
527.6
525.6
GROUP V
Liver Wt. 19.563 15.623 17.617
21.739 20.699
Relative Liver to Body Wt. 0.045
0.038
0.035
0.041
0.039
Test Day
52 52 52 52 52
Animal Number 627281
627297 627303
627305
627308
Final
Body Wt. 574.3
531.5
512.5
743.2
598.6
GROUP VI
Liver Wt. 18.730 18.196 16.634 27.873 19.317
Relative Liver to Body Wt.
0.033 0.034 0.032 0.038 0.032
Test Day
94 94
94 94
94
-33-
Company Sanitized. Does not contain TSCA CBI
H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement No. 1
APPENDIX B
Individual Fluorine Levels
-34- CaEspaay Sanitized. Does not contain TSCA CB1
Terms: Active % Active
TERMS AND CALCULATIONS
Mol Wt Active
Formulation Dose % P in Active
MolWtF
Compound Calculations:
Dose Active (mg/kg)
The mg of fluorine containing compound administered per kg of animal body weight.
= (% active/100) x Formulation Dose
Dose Active (mmole/kg)
The mmole of fluorine containing compound administered per kg of animal body weight
= dose [mg/kg] / Mol Wt Active [mg/mmol]
Dose F (mg/kg)
The mg Fluorine administered per kg of animal body weight = (% F in active/100) x Dose Active [mg/kg]
Dose F (mmol/kg)
The mmole of fluorine administered per kg of animal body weight = Dose F [mg/kg] / Mol Wt F [mg/mmol]
Molar Ratio (Active/P)
The moles of fluorine containing compound per mole of fluorine = Dose Active [mmol/kg] / Dose P [mmol/kg]
Formulation Dose Normalization Factor
The formulation dose that would be required to administer the amount of active needed to achieve the normalized dose
= (Normalized dose of Active [mmol/kg] / Dose Active [mmol/kg]) x Formulation Dose
-35- Company Saait'szed. Does not contain TSCACBI
H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement No. 1
TERMS AND CALCULATIONS
Individual Animal Measurement:
ppm F in liver
The ppm fluoride measured in liver
Individual Animal Calculations:
ppm F in Liver minus Bkg 0.2 ppm
ppm F in liver
normalized to 0.1 mmol/kg Dose
The ppm fluoride measured in liver minus the background fluoride measured in control animal liver. In this case the value was established at 0.2 ppm.
The ppm fluoride minus background that would be expected if the active dose was 0.1 mmol/kg instead of the actual active dose. This assumes linearity between administered dose and liver fluorine levels, but is needed because different doses of active were used in the study.
= (0.1 [mmol/kg] /Active dose [mmol/kg]) x (ppm F in liver
minus background)
/zmolar equivalents of active in liver
The /xmolar [^mol/L] concentration of fluorine containing compound
in liver based on the ppm fluorine in liver normalized to 0.1 mmol/kg active dose. This assumes that all liver fluorine is derived from the fluorine-containing component in the formulation. Note: 1 ppm -
Img/L = (Normalized ppm [mg/L] fluorine in liver / Mol Wt F
[mg/mmol]) x molar ratio active/F [mmol active/mmol F] x 1000 /imol/mmol
36- Compaq Sashed. Qoes not contain TSCA.CBS
H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
DuPont-2931 Supplement No. 1
FACTORS INFLUENCING INTERPRETATION OF KINETIC ANALYSIS
Considerations:
- The data used for kinetic analysis was from a limited screen and extrapolation should be done
cautiously. - Sample size is low - Analytical data used without validation - Steady-state not reached - Terminal phase may not be reached
- Some compounds are mixtures of fluorinated compounds - Different active and formulation doses were used - Different vehicles were used to deliver formulations - Each compound may have very different potency for producing toxicity
Assumptions: (May or may not be justified in all cases)
- Liver fluorine concentrations are linear with respect to dose - Analytical method is appropriate for all types of compounds - Elimination kinetics can be determined based on total fluorine rather than on concentrations of
individual components - Background Fluorine is 0.2 ppm
- % F data is the % Fluorine of the active (Fluorine containing components) in the formulation) - Molecular weight is the molecular weight of the active component in the formulation
Company SanitizetLDoesiiQtcsyitaJB-TSCA.CBi
H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-24019
DuPont-2931 Supplement No. 1
Given:
Mol Wt. Active (g/mole):
497
Formulation Dose (mg/kg):
10
% Active (F Containing) in Formulation: 100
%F in Active:
65
Mol Wt.F(g/mol):
19
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg): Formulation Dose Normalization Factor:
10 0.020 49.7
DoseF(mmol/kg):
0.342
Molar Ratio (Active/F): 0.059
Dose F (mg/kg):_____6.5
Rat Number
Test Day Sample
ppmF
in Liver
Group II
625320
10
319.4
625330
10
355.4
625332
10
338.4
625341
10
305.0
625350
10
322.7
ppmF in Liver
Minus Bkg 0.2 ppm
319.2 355.2 338.2 304.8 322.5
Group VI
625326
94
625335
94
625346
94
625347
94
625351
94
79.8 89.6 73.8 62.5 82.1
79.6 89.4 73.6 62.3 81.9
ppm F in Liver Normalized to 0.1 mmoles/kg
Dose
1586.42 1765.34 1680.85 1514.86 1602.83
395.61 444.32 365.79 309.63 407.04
/(molar Equivalents of Active in
Liver
4910.77 5464.62 5203.08 4689.23 4961.54
1224.62 1375.38 1132.31 958.46 1260.00
-38-
Company Sanitized. Does not contain T3CA CB1
H-24042: Biopersistence Screening 10-Dose Oral Gavage Study in Rats
Data for H-24020
DuPont-2931 Supplement No. 1
Given:
Mol Wt. Active (g/mole):
426
Formulation Dose (mg/kg):
20
% Active (F Containing) in Formulation: 100
% F in Active:
69
MolWt.F(g/mol):
19
Calculated Values: Dose Active (mg/kg): Dose Active (mmole/kg):
Formulation Dose Normalization Factor:
20 0.047 42.6
DoseF(mmol/kg):
0.726
Molar Ratio (Active/F): 0.065
Dose F (mg/kg):_____13.8
Rat Number
Test Day Sample
ppmF
in
Liver
Group II
627768
10
627774
10
627776
10
627782
10
627785
10
182.5 109.0 174.0 147.5 165.8
ppmF in Liver
Minus Bkg 0.2 ppm
182.3 108.8 173.8 147.3 165.6
Group VI
627778
94
1.9
1.7
627783
94
1.2
1.0
627762
94
1.9
1.7
627775
94
1.6
1.4
627769
94
1.8
1.6
ppm F in Liver Normalized to
0.1 mmoles/kg Dose
388.30 231.74 370.19 313.75 352.73
3.62 2.13 3.62 2.98 3.41
fimolar Equivalents of Active in
Liver
1321.01 788.41
1259.42 1067.39 1200.00
12.32 7.25
12.32 10.14 11.59
-39-
Company Sanitized. Does not contain TBCA CBI
11204-D0o4s2e:OrBailopGearvsaigsteenScte yScrieneRnaiinsg
SuppDleumpeonntt N2o9.31|
-
Data for H-24042
-- Give`nMo:l We. Active (g/mole): 531 % Fin Active: 75
Formulation Dose (mg/kg):
100 Mol Wi F (g/mol): 19
9% Active (F Containing) in Formulation: 100
CalcDuolsaeteAdctViavleue(sm:g/kg):
100
FDoorsmeulAacttiiovneD(omsmoelNeo/rkmea)l:ization Factor:
0.188 53.1
Dose F (mmol/kg): 3.947
Molar Ratio (Active/): 0.048
Dose F (mg/kg):
75
Test ppmF Rat Day in Number Sample _ Liver
ppm Fin ppm F in Liver
Liver MinusBkg ~~
Normalized to 0.1 mmoleskg
0.2 ppm
Dose
molar Equivalents of Activein
Liver
Group II 6278 10 1949
1947
10339
259.60
-
627289 10 2340
238
no 10 2141
2139
124.15 113.58
31173 285.20
6793 10 1821 621309 10 1936
1819 193.4
96.59 10270
24253 25787
Group VI 62781 9% 103
10.1
536
13.47
627297 m3
9% 94
114 122
12 120
595 637
14.93 1600
627305 94 149 627308 94 90
147 88
781 467
19.60 173
----
_
o`CompanySanilizad. 009snotcontainTSCACBI